Case: A 72-year-old gentleman presents to your emergency department. He has been generally unwell for around one week, with a worsening cough, shortness of breath and fever. He is now feeling extremely short of breath, appears confused and is pyrexial at 39 degrees centigrade. His observations are heart rate of 102 beats per minute, respiratory rate of 34 breaths per minute, blood pressure of 110/67 mmHg, and oxygen saturation of 91% on room air.

Background: There have been a large number of trials on steroids for a variety of conditions in the last year and we have covered some of them on the SGEM:

The ADRENAL trial on steroids in septic shock demonstrating no all-cause mortality benefit at 90 days (SGEM#208).

Oral prednisolone in preschool children with virus-associated wheeze showed a decrease in emergency department length-of-stay with steroids compared to placebo (SGEM#206).

A single dose of dexamethasone was non-inferior to a three-day course of oral prednisolone in the treatment of children with an acute asthma exacerbation (SGEM#194).

The Cochrane collaboration has come out with yet another paper on our favourite panacea, the steroid. This time, it is a systematic review and meta-analysis looking at the effects of steroids in patients presenting with a community acquired pneumonia.

This is an update from their previous review on the topic published in 2011. It showed that in most patients with pneumonia, corticosteroids are beneficial for accelerating the time to resolution of symptoms, but lacked enough data to make any recommendations.

“In most patients with pneumonia, corticosteroids are generally beneficial for accelerating the time to resolution of symptoms. However, evidence from the included studies was not strong enough to make any recommendations.” [1]

Clinical Question: Do steroids safely reduce morbidity and mortality in patients with community acquired pneumonia?

Population: Adults and or children presenting to the emergency department or primary care settings with a diagnosis of community acquired pneumonia confirmed radiographically.

Exclusions: Studies including only neonates, patients with Pneumocystis pneumonia, and patients with HIV.

Intervention: Systemic corticosteroids given at any dose, by any mode and for any duration. Steroids that were included were: prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, and hydrocortisone.

Comparison: Placebo or no corticosteroids.

Outcome:

Primary Outcome: All-cause mortality at 30 days after randomization. If 30-day mortality not reported then the outcome closest to 30-days was used.

Secondary Outcomes: They had ten secondary outcomes.

Do corticosteroids reduce morbidity among people with community acquired pneumonia?

Do corticosteroids increase complication rates among people with community acquired pneumonia?

Authors’ Conclusions:“Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.”

Quality Check List for Therapeutic Systematic Reviews:

The clinical question is sensible and answerable. Yes

The search for studies was detailed and exhaustive. Yes

The primary studies were of high methodological quality. Yes

The assessment of studies were reproducible. Yes

The outcomes were clinically relevant. Yes

There was low statistical heterogeneity for the primary outcomes. Yes

The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results:They identified 17 RCTs (n=2,264) with community-acquired pneumonia to include in this SRMA. The majority or the trials (13) were in adults with only 4 (n=310) in children.

Adverse Events: No significant differences except for significantly more hyperglycemia in the corticosteroid group

As you’d expect from a Cochrane systematic review, the paper is pretty well done. I like the fact that one of their stated secondary outcomes was to look at complications from the corticosteroids, as we know that side effects and harms of treatment are often overlooked or under-reported.

External Validity: This was a strong systematic review looking at lots of studies from all over the planet. The trials were conducted worldwide: eight in Europe, four in China or Japan, three in the Middle East, and one each in South Africa and Australia. Four of the 17 trials included in the SRMA were done in children. This makes it a very generalizable outcome and more likely to apply to most patient populations.

Patient Oriented Outcomes: Mortality is a very dichotomous patient-oriented outcome. They also looked at the mostly dead (morbidity) and considered time to cure, hospital length of stay, complications, transfer to the ICU, clinical failure and adverse events.

Bias: Almost all of the trials (14/17) had a high risk of reporting bias. This type bias when the nature and direction of the results influence the dissemination of the research. There are a number of types of reporting biases (publication bias, time lag bias, duplicate publication bias, location bias, citation bias, language bias, outcome reporting bias, etc). It is well recognized that positive trials are more likely to be published and published quicker than negative trials [2]. This type of bias can be compounded when put into a SRMA. They authors explored the possibility of small-study and publication biases using a funnel plot. No small-studies effect was demonstrated in the funnel plot analysis.

COPD Patients: We know that COPD patients commonly present with chest infections and pneumonia, and these patients are known to benefit from steroids. The authors of this study were unable to separate out the patients with COPD from those without. It is possible, although I feel unlikely, that much of the benefit of corticosteroids came from patients with pneumonia and COPD.

Unknowns: Despite this new SRMA containing more data there is still a number of unknowns:

The number of children included in the review was small and the mortality event rate was low. This makes it difficult to comment on the impact of corticosteroids in this population.

The trials used a variety of corticosteroids, doses and duration. Therefore, while the effect is consistent across different regiments it is unclear what the optimal management would be.

Corticosteroids seem to have an effect on all-cause mortality in adults admitted with CAP. This effect is increased in the group with more severe pneumonia. However, the studies of corticosteroids for undifferentiated patients with sepsis have not demonstrated a clear mortality benefit?

There was a lack of data in the included trials to perform most of the predefined subgroup analyses. Subgroup analyses can be hypothesis generating. Based on the information provided we do not know what the net effect corticosteroids would have on certain patient populations (ex. diabetics, elderly, viral pneumonia, hospital acquired pneumonia, etc).

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusion.

Case Resolution: I start the patient on IV co-amoxiclav and oral clarithromycin, as well as giving 40mg of oral prednisolone for seven days.

Clinical Application: For patients with severe community acquired pneumonia, consider giving corticosteroids (40-50mg or prednisone per day) for seven to ten days as an adjunct to their antibiotics.

Dr. Jake Turner

What Do I Tell My Patient? It looks like you have a severe pneumonia. This is a type of chest infection with bacteria in your lungs. We are going to give you two types of antibiotics to help fight the pneumonia. I’m going to give you another medicine called a corticosteroid. It is a stress hormone that your body naturally makes when you are sick. We are just going to give you a little more for a few days. There is good evidence that this extra stress hormone can decrease your risk of dying and speed up your recovery. The main risk is that it might make your blood sugars go higher. We will keep an eye on your blood sugar and it is unlikely to cause a major problem.

Keener Kontest: Last weeks’ winner was Jarek Gucwa from Poland. He knew King George II of England was the first person to be formally diagnosed on autopsy of having suffered an aortic dissection.

Listen to the SGEM podcast on iTunes to hear this weeks’ question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.